- Email: [email protected]
Antiglutamatergic therapy for multiple sclerosis?
Comment
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Young GB, Jordan KG, Doig GS. An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: an investigation of variables associated with mortality. Neurology 1996; 47: 83–89. Chong DJ, Hirsch LJ. Which EEG patterns warrant treatment in the critically ill? Reviewing the evidence for treatment of periodic epileptiform discharges and related patterns. J Clin Neurophysiol 2005; 22: 79–91. Kaplan PW. EEG criteria for nonconvulsive status epilepticus. Epilepsia 2007; 48 (suppl 8): 39–41. Hirsch LJ, LaRoche SM, Gaspard N, et al. American Clinical Neurophysiology Society’s Standardized Critical Care EEG Terminology: 2012 version. J Clin Neurophysiol 2013; 30: 1–27.
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Beniczky S, Hirsch LJ, Kaplan PW, et al. Unified EEG terminology and criteria for nonconvulsive status epilepticus. Epilepsia 2013; 54 (suppl 6): 28–29. Leitinger M, Trinka E, Gardella E, et al. Diagnostic accuracy of the Salzburg EEG criteria for non-convulsive status epilepticus: a retrospective study. Lancet Neurol 2016; 15: 1054–62. Husain AM. Lacosamide in status epilepticus: Update on the TRENdS study. Epilepsy Behav 2015; 49: 337–39.
Antiglutamatergic therapy for multiple sclerosis? More than a dozen anti-inflammatory agents are available (or will soon be approved) for the treatment of relapsing-remitting multiple sclerosis. These immunomodulatory therapies not only reduce the frequency of exacerbations but also slow progression of neurological impairment, suggesting that they exert indirect neuroprotective effects. None, however, seems capable of directly protecting axons and neurons. Unsurprisingly, therefore, these drugs are mostly ineffective in the treatment of primary and secondary progressive multiple sclerosis. One notable exception is the B-cell-depleting monoclonal antibody ocrelizumab, which significantly slowed disease progression in a phase 3 trial in patients with primary progressive multiple sclerosis.1 This finding suggests that, even in progressive multiple sclerosis, inflammatory mechanisms contribute to disease pathogenesis. One of the biggest challenges in multiple sclerosis research is to identify treatments that provide direct neuronal protection. Not only is this challenge a holy grail for multiple sclerosis, as more than half of the patients have progressive forms of disease, but for neurological therapeutics in general. In a Personal View in The Lancet Neurology, Richard Macrez and colleagues2 propose that glutamate could be a promising target for multiple sclerosis therapy. Excitotoxicity has been explored as a therapeutic target since the 1980s, especially in acute stroke, although, despite intense research, no effective neuroprotective therapy has been identified.3 Why antiglutamatergic therapy might work in multiple sclerosis could, therefore, be questioned. Macrez and colleagues argue that glutamate is involved in many of the key pathophysiological processes in multiple sclerosis, including axonal damage, oligodendroglial and myelin pathology, and dysfunction of the blood–brain barrier. Thus, targeting excess glutamate could provide a master www.thelancet.com/neurology Vol 15 September 2016
switch for reducing immune-cell infiltration into the CNS, at the same time limiting the damage to resident cells of the CNS inflicted by any immune cells that manage to cross the brain-blood barrier. Although such a polyvalent therapeutic strategy is undoubtedly attractive, and is eloquently argued by the authors, several unanswered questions remain concerning the pathological basis of glutamate excitotoxicity in multiple sclerosis and the clinical strategies for targeting it in patients. For example, whether glutamate is the major molecular intermediate of immune-mediated axon damage, and whether and how it interacts with other potentially toxic intermediates released by activated immune cells will be important to clarify.4 Likewise, studies are required to assess whether and how glutamate directly contributes to grey-matter pathology in multiple sclerosis. Glutamate release and scavenging have been reported to be altered in animal models of neuroinflammatory disorders, and glutamate receptors are prominently expressed at synapses.5,6 Speculating that pathological activation of these receptors (and their extrasynaptic counterparts) mediates the prominent dendritic and synaptic pathology seen in advanced stages of multiple sclerosis is, therefore, tempting. In parallel to elucidating the mechanistic basis for antiglutamatergic strategies in multiple sclerosis, the best way to target excessive glutamate in the inflamed CNS needs to be established. This information seems especially pertinent in light of the emerging role of glutamate signalling, not only in neurotransmission but also in metabolic coupling of the axon-myelin unit.7 As Macrez and colleagues acknowledge,2 various refined strategies are now available to differentiate between the physiological and pathological actions of glutamate, which provides hope that the results of future clinical trials will be more promising than the so far rather disappointing experience
See Personal View page 1089
1003
Comment
For the International Progressive MS Alliance see http://www. progressivemsalliance.org/
with antiglutamatergic therapies. Such trials of multiple sclerosis are likely to focus on the progressive stage of the disease, where neurodegenerative mechanisms seem to have prominent roles and effective therapeutic strategies are badly needed. Indeed, due to various activities, not least those of the International Progressive MS Alliance, there has been a remarkable surge of awareness for the unmet needs of people with progressive multiple sclerosis. Clearly, a precise understanding of the mechanisms of neurodegeneration in progressive multiple sclerosis is an essential prerequisite for achieving therapeutic progress. In this regard, glutamatergic mechanisms are certainly not the only potential target. Others include voltage-gated sodium channels (as a target for phenytoin8) and other ion channels,4 metabolic pathways (eg, as targets for high-dose biotin9 and statins10), and remyelination.11 With intensified research, the aim of finding a neuroprotective therapy for progressive multiple sclerosis might not be unrealistic. *Reinhard Hohlfeld, Martin Kerschensteiner Institute of Clinical Neuroimmunology, Biomedical Centre and University Hospital, Ludwig Maximilians University, Munich D-81377, Germany (RH, MK); and Munich Cluster of Systems Neurology (SyNergy), Munich, Germany (RH, MK) [email protected]
RH has received grant support or personal fees from Actelion, Bayer, Biogen, Genzyme-Sanofi, Medday, Merck-Serono, Novartis, Roche, and Teva. MK has received grant support or personal fees from Biogen, Genzyme-Sanofi, Merck-Serono, and Novartis. RH and MK are supported by the German Research Foundation (DFG: TRR 128, SPP 1710, EXC 1010), German Ministry for Education and Research (BMBF; German Competence Network Multiple Sclerosis), the European Research Council under the European Union Seventh Framework Program (FP/2007-2013; ERC grant agreement 310932), the Hertie Foundation, Verein Therapieforschung für Multiple Sklerose Kranke, and Cyliax Stiftung. 1
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Fernandez O, Rodriguez-Antiguedad A, Olascoaga J, et al. Review of the novelties from the 31st ECTRIMS Congress, 2015, presented at the 8th Post-ECTRIMS meeting. Rev Neurol 2016; 62: 559–69. Macrez R, Stys, PK, Vivien D, Lipton SA, Docagne F. Mechanisms of glutamate toxicity in multiple sclerosis: biomarker and therapeutic opportunities. Lancet Neurol 2016; 15: 1089–102. Chamorro A, Dirnagl U, Urra X, Planas AM. Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol 2016; 15: 869–81. Friese MA, Schattling B, Fugger L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol 2014; 10: 225–38. Dutta R, Chang A, Doud MK, et al. Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients. Ann Neurol 2011; 69: 445–54. Jurgens T, Jafari M, Kreutzfeldt M, et al. Reconstruction of single cortical projection neurons reveals primary spine loss in multiple sclerosis. Brain 2016; 139: 39–46. Saab AS, Tzvetavona ID, Trevisiol A, et al. Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism. Neuron 2016; 91: 119–32. Raftopoulos R, Hickman SJ, Toosy A, et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2016; 15: 259–69. Sedel F, Bernard D, Mock DM, Tourbah A. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology 2015; published online Sept 5. DOI:10.1016/j.neuropharm.2015.08.028. Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21. Kremer D, Gottle P, Hartung HP, Kury P. Pushing forward: remyelination as the new frontier in CNS diseases. Trends Neurosci 2016; 39: 246–63.
Corrections Published Online February 1, 2016 http://dx.doi.org/10.1016/ S1474-4422(16)00036-3 Published Online February 3, 2016 http://dx.doi.org/10.1016/ S1474-4422(16)00058-2 Published Online July 11, 2016 http://dx.doi.org/10.1016/ S1474-4422(16)30161-2
1004
Ranscombe P. Lessons learned from Christmas lectures. Lancet Neurol 2016; http://dx.doi.org/10.1016/S1474-4422(16)00008-9—The amount of UK Government spending on mental health should be £9·75. This correction has been made to the online version as of Feb 1, 2016. Ranscombe P. Lessons learned from Christmas lectures. Lancet Neurol 2016; http://dx.doi.org/10.1016/S1474-4422(16)00008-9—The amount boosted by cancer research charities per £1 of government spending should be £2·75. This correction has been made to the online version as of Feb 3, 2016. Koy A, JP Lin, T D Sanger, W A Marks , J W Mink, L Timmermann. Advances in management of movement disorders in children. Lancet Neurol 2016; 15: 719–35—In the table of this Review, the dose range for intrathecal baclofen should read “100–1000 μg”. Also, the final indication for treatment of myoclonus with clonazepam should read “segmental and propriospinal myoclonus”; the final indication for treatment of myoclonus with 5-hydroxytryptophan and tetrabenazine should read “segmental myoclonus”; the first indication for treatment of myoclonus with trihexyphenidyl and botulinum toxin A should read “segmental myoclonus”; the indication for treatment of myoclonus with ethosuximide should read “cortico-subcortical myoclonus”, references 2, 6, and 7 at the end of Ethosuximide treatment should be replaced with reference 63; and the authors and editors of reference 4 should be “Singer HS, Mink JW, Gilbert DL, Jankovic J”. These corrections have been made to the online version as of July 11, 2016.
www.thelancet.com/neurology Vol 15 September 2016
4
5
6 7
Young GB, Jordan KG, Doig GS. An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: an investigation of variables associated with mortality. Neurology 1996; 47: 83–89. Chong DJ, Hirsch LJ. Which EEG patterns warrant treatment in the critically ill? Reviewing the evidence for treatment of periodic epileptiform discharges and related patterns. J Clin Neurophysiol 2005; 22: 79–91. Kaplan PW. EEG criteria for nonconvulsive status epilepticus. Epilepsia 2007; 48 (suppl 8): 39–41. Hirsch LJ, LaRoche SM, Gaspard N, et al. American Clinical Neurophysiology Society’s Standardized Critical Care EEG Terminology: 2012 version. J Clin Neurophysiol 2013; 30: 1–27.
8 9
10
Beniczky S, Hirsch LJ, Kaplan PW, et al. Unified EEG terminology and criteria for nonconvulsive status epilepticus. Epilepsia 2013; 54 (suppl 6): 28–29. Leitinger M, Trinka E, Gardella E, et al. Diagnostic accuracy of the Salzburg EEG criteria for non-convulsive status epilepticus: a retrospective study. Lancet Neurol 2016; 15: 1054–62. Husain AM. Lacosamide in status epilepticus: Update on the TRENdS study. Epilepsy Behav 2015; 49: 337–39.
Antiglutamatergic therapy for multiple sclerosis? More than a dozen anti-inflammatory agents are available (or will soon be approved) for the treatment of relapsing-remitting multiple sclerosis. These immunomodulatory therapies not only reduce the frequency of exacerbations but also slow progression of neurological impairment, suggesting that they exert indirect neuroprotective effects. None, however, seems capable of directly protecting axons and neurons. Unsurprisingly, therefore, these drugs are mostly ineffective in the treatment of primary and secondary progressive multiple sclerosis. One notable exception is the B-cell-depleting monoclonal antibody ocrelizumab, which significantly slowed disease progression in a phase 3 trial in patients with primary progressive multiple sclerosis.1 This finding suggests that, even in progressive multiple sclerosis, inflammatory mechanisms contribute to disease pathogenesis. One of the biggest challenges in multiple sclerosis research is to identify treatments that provide direct neuronal protection. Not only is this challenge a holy grail for multiple sclerosis, as more than half of the patients have progressive forms of disease, but for neurological therapeutics in general. In a Personal View in The Lancet Neurology, Richard Macrez and colleagues2 propose that glutamate could be a promising target for multiple sclerosis therapy. Excitotoxicity has been explored as a therapeutic target since the 1980s, especially in acute stroke, although, despite intense research, no effective neuroprotective therapy has been identified.3 Why antiglutamatergic therapy might work in multiple sclerosis could, therefore, be questioned. Macrez and colleagues argue that glutamate is involved in many of the key pathophysiological processes in multiple sclerosis, including axonal damage, oligodendroglial and myelin pathology, and dysfunction of the blood–brain barrier. Thus, targeting excess glutamate could provide a master www.thelancet.com/neurology Vol 15 September 2016
switch for reducing immune-cell infiltration into the CNS, at the same time limiting the damage to resident cells of the CNS inflicted by any immune cells that manage to cross the brain-blood barrier. Although such a polyvalent therapeutic strategy is undoubtedly attractive, and is eloquently argued by the authors, several unanswered questions remain concerning the pathological basis of glutamate excitotoxicity in multiple sclerosis and the clinical strategies for targeting it in patients. For example, whether glutamate is the major molecular intermediate of immune-mediated axon damage, and whether and how it interacts with other potentially toxic intermediates released by activated immune cells will be important to clarify.4 Likewise, studies are required to assess whether and how glutamate directly contributes to grey-matter pathology in multiple sclerosis. Glutamate release and scavenging have been reported to be altered in animal models of neuroinflammatory disorders, and glutamate receptors are prominently expressed at synapses.5,6 Speculating that pathological activation of these receptors (and their extrasynaptic counterparts) mediates the prominent dendritic and synaptic pathology seen in advanced stages of multiple sclerosis is, therefore, tempting. In parallel to elucidating the mechanistic basis for antiglutamatergic strategies in multiple sclerosis, the best way to target excessive glutamate in the inflamed CNS needs to be established. This information seems especially pertinent in light of the emerging role of glutamate signalling, not only in neurotransmission but also in metabolic coupling of the axon-myelin unit.7 As Macrez and colleagues acknowledge,2 various refined strategies are now available to differentiate between the physiological and pathological actions of glutamate, which provides hope that the results of future clinical trials will be more promising than the so far rather disappointing experience
See Personal View page 1089
1003
Comment
For the International Progressive MS Alliance see http://www. progressivemsalliance.org/
with antiglutamatergic therapies. Such trials of multiple sclerosis are likely to focus on the progressive stage of the disease, where neurodegenerative mechanisms seem to have prominent roles and effective therapeutic strategies are badly needed. Indeed, due to various activities, not least those of the International Progressive MS Alliance, there has been a remarkable surge of awareness for the unmet needs of people with progressive multiple sclerosis. Clearly, a precise understanding of the mechanisms of neurodegeneration in progressive multiple sclerosis is an essential prerequisite for achieving therapeutic progress. In this regard, glutamatergic mechanisms are certainly not the only potential target. Others include voltage-gated sodium channels (as a target for phenytoin8) and other ion channels,4 metabolic pathways (eg, as targets for high-dose biotin9 and statins10), and remyelination.11 With intensified research, the aim of finding a neuroprotective therapy for progressive multiple sclerosis might not be unrealistic. *Reinhard Hohlfeld, Martin Kerschensteiner Institute of Clinical Neuroimmunology, Biomedical Centre and University Hospital, Ludwig Maximilians University, Munich D-81377, Germany (RH, MK); and Munich Cluster of Systems Neurology (SyNergy), Munich, Germany (RH, MK) [email protected]
RH has received grant support or personal fees from Actelion, Bayer, Biogen, Genzyme-Sanofi, Medday, Merck-Serono, Novartis, Roche, and Teva. MK has received grant support or personal fees from Biogen, Genzyme-Sanofi, Merck-Serono, and Novartis. RH and MK are supported by the German Research Foundation (DFG: TRR 128, SPP 1710, EXC 1010), German Ministry for Education and Research (BMBF; German Competence Network Multiple Sclerosis), the European Research Council under the European Union Seventh Framework Program (FP/2007-2013; ERC grant agreement 310932), the Hertie Foundation, Verein Therapieforschung für Multiple Sklerose Kranke, and Cyliax Stiftung. 1
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Fernandez O, Rodriguez-Antiguedad A, Olascoaga J, et al. Review of the novelties from the 31st ECTRIMS Congress, 2015, presented at the 8th Post-ECTRIMS meeting. Rev Neurol 2016; 62: 559–69. Macrez R, Stys, PK, Vivien D, Lipton SA, Docagne F. Mechanisms of glutamate toxicity in multiple sclerosis: biomarker and therapeutic opportunities. Lancet Neurol 2016; 15: 1089–102. Chamorro A, Dirnagl U, Urra X, Planas AM. Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol 2016; 15: 869–81. Friese MA, Schattling B, Fugger L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol 2014; 10: 225–38. Dutta R, Chang A, Doud MK, et al. Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients. Ann Neurol 2011; 69: 445–54. Jurgens T, Jafari M, Kreutzfeldt M, et al. Reconstruction of single cortical projection neurons reveals primary spine loss in multiple sclerosis. Brain 2016; 139: 39–46. Saab AS, Tzvetavona ID, Trevisiol A, et al. Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism. Neuron 2016; 91: 119–32. Raftopoulos R, Hickman SJ, Toosy A, et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2016; 15: 259–69. Sedel F, Bernard D, Mock DM, Tourbah A. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology 2015; published online Sept 5. DOI:10.1016/j.neuropharm.2015.08.028. Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21. Kremer D, Gottle P, Hartung HP, Kury P. Pushing forward: remyelination as the new frontier in CNS diseases. Trends Neurosci 2016; 39: 246–63.
Corrections Published Online February 1, 2016 http://dx.doi.org/10.1016/ S1474-4422(16)00036-3 Published Online February 3, 2016 http://dx.doi.org/10.1016/ S1474-4422(16)00058-2 Published Online July 11, 2016 http://dx.doi.org/10.1016/ S1474-4422(16)30161-2
1004
Ranscombe P. Lessons learned from Christmas lectures. Lancet Neurol 2016; http://dx.doi.org/10.1016/S1474-4422(16)00008-9—The amount of UK Government spending on mental health should be £9·75. This correction has been made to the online version as of Feb 1, 2016. Ranscombe P. Lessons learned from Christmas lectures. Lancet Neurol 2016; http://dx.doi.org/10.1016/S1474-4422(16)00008-9—The amount boosted by cancer research charities per £1 of government spending should be £2·75. This correction has been made to the online version as of Feb 3, 2016. Koy A, JP Lin, T D Sanger, W A Marks , J W Mink, L Timmermann. Advances in management of movement disorders in children. Lancet Neurol 2016; 15: 719–35—In the table of this Review, the dose range for intrathecal baclofen should read “100–1000 μg”. Also, the final indication for treatment of myoclonus with clonazepam should read “segmental and propriospinal myoclonus”; the final indication for treatment of myoclonus with 5-hydroxytryptophan and tetrabenazine should read “segmental myoclonus”; the first indication for treatment of myoclonus with trihexyphenidyl and botulinum toxin A should read “segmental myoclonus”; the indication for treatment of myoclonus with ethosuximide should read “cortico-subcortical myoclonus”, references 2, 6, and 7 at the end of Ethosuximide treatment should be replaced with reference 63; and the authors and editors of reference 4 should be “Singer HS, Mink JW, Gilbert DL, Jankovic J”. These corrections have been made to the online version as of July 11, 2016.
www.thelancet.com/neurology Vol 15 September 2016